Dementia in multiple sclerosis: report of a case with cortical grey matter involvement and frontal-type-like clinical features

Background/introductionAlthough multiple sclerosis (MS), a demyelinating disease of unknown aetiology, is primarily a white matter disease, it may also involve the grey matter, a feature not often demonstrated in vivo by means of magnetic resonance imaging (MRI). The involvement of cortical grey matter in MS may account for cognitive dysfunction and behavioural abnormalities.ObjectiveThe purpose of this report is to present the case of a patient with MS and clinical features mimicking dementia of the frontal type due to clear-cut cortical grey matter involvement in the left frontal lobe.Case reportA 55-year-old woman with relapsing remitting MS developed a clinical picture characterized by frontal deficits (e.g. attention, verbal fluency, and speed processing), disinhibition, loss of insight, perseveration, abnormal eating behaviour, agitation, insomnia, and depersonalization phenomena. Neuropsychological evaluation also revealed abnormal performance on the Trail Making and the Stroop tests. Besides typical demyelinating lesions and “black holes”, MRI showed a striking pattern of left frontal opercular involvement including cortical thinning, focal knife-edge appearance of the gyri, and marked gliosis in the adjacent white matter.DiscussionCognitive deficits in MS are typically subcortical, due to the expected predominance of white matter lesions. Nonetheless, the involvement of grey matter structures may contribute to a different pattern of cognitive dysfunction. For example, hippocampal involvement has been linked to memory impairment. This particular case report additionally illustrates how cortical grey matter involvement in the frontal lobe may lead (not unexpectedly) to a clinical condition mostly characterised by frontal deficits and psychiatric symptoms.

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Multi-parametric structural magnetic resonance imaging in relation to cognitive dysfunction in long-standing multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458515596598 ◽

2015 ◽

Vol 22 (5) ◽

pp. 608-619 ◽

Cited By ~ 23

Author(s):

Marita Daams ◽

Martijn D Steenwijk ◽

Menno M Schoonheim ◽

Mike P Wattjes ◽

Lisanne J Balk ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Cognitive Dysfunction ◽

Cognitive Deficits ◽

Grey Matter ◽

White Matter Damage ◽

Diffuse White Matter ◽

Brain White Matter ◽

Deep Grey Matter ◽

Imaging Markers

Background: Cognitive deficits are common in multiple sclerosis. Most previous studies investigating the imaging substrate of cognitive deficits in multiple sclerosis included patients with relatively short disease durations and were limited to one modality/brain region. Objective: To identify the strongest neuroimaging predictors for cognitive dysfunction in a large cohort of patients with long-standing multiple sclerosis. Methods: Extensive neuropsychological testing and multimodal 3.0T MRI was performed in 202 patients with multiple sclerosis and 52 controls. Cognitive scores were compared between groups using Z-scores. Whole-brain, white matter, grey matter, deep grey matter and lesion volumes; cortical thickness, (juxta)cortical and cerebellar lesions; and extent and severity of diffuse white matter damage were measured. Stepwise linear regression was used to identify the strongest predictors for cognitive dysfunction. Results: All cognitive domains were affected in patients. Patients showed extensive atrophy, focal pathology and damage in up to 75% of the investigated white matter. Associations between imaging markers and average cognition were two times stronger in cognitively impaired patients than in cognitively preserved patients. The final model for average cognition consisted of deep grey matter DGMV volume and fractional anisotropy severity (adjusted R²=0.490; p<0.001). Conclusion: From all imaging markers, deep grey matter atrophy and diffuse white matter damage emerged as the strongest predictors for cognitive dysfunction in long-standing multiple sclerosis.

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Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter

Acta Neuropathologica ◽

10.1007/s00401-021-02274-7 ◽

2021 ◽

Vol 141 (4) ◽

pp. 585-604 ◽

Cited By ~ 1

Author(s):

Carmen Picon ◽

Anusha Jayaraman ◽

Rachel James ◽

Catriona Beck ◽

Patricia Gallego ◽

...

Keyword(s):

Multiple Sclerosis ◽

Signaling Pathway ◽

Cortical Neurons ◽

Grey Matter ◽

Molecular Mechanisms ◽

Fold Increase ◽

Cell Types ◽

Meningeal Inflammation ◽

Cortical Grey Matter

AbstractSustained exposure to pro-inflammatory cytokines in the leptomeninges is thought to play a major role in the pathogenetic mechanisms leading to cortical pathology in multiple sclerosis (MS). Although the molecular mechanisms underlying neurodegeneration in the grey matter remain unclear, several lines of evidence suggest a prominent role for tumour necrosis factor (TNF). Using cortical grey matter tissue blocks from post-mortem brains from 28 secondary progressive MS subjects and ten non-neurological controls, we describe an increase in expression of multiple steps in the TNF/TNF receptor 1 signaling pathway leading to necroptosis, including the key proteins TNFR1, FADD, RIPK1, RIPK3 and MLKL. Activation of this pathway was indicated by the phosphorylation of RIPK3 and MLKL and the formation of protein oligomers characteristic of necrosomes. In contrast, caspase-8 dependent apoptotic signaling was decreased. Upregulation of necroptotic signaling occurred predominantly in macroneurons in cortical layers II–III, with little expression in other cell types. The presence of activated necroptotic proteins in neurons was increased in MS cases with prominent meningeal inflammation, with a 30-fold increase in phosphoMLKL+ neurons in layers I–III. The density of phosphoMLKL+ neurons correlated inversely with age at death, age at progression and disease duration. In vivo induction of chronically elevated TNF and INFγ levels in the CSF in a rat model via lentiviral transduction in the meninges, triggered inflammation and neurodegeneration in the underlying cortical grey matter that was associated with increased neuronal expression of TNFR1 and activated necroptotic signaling proteins. Exposure of cultured primary rat cortical neurons to TNF induced necroptosis when apoptosis was inhibited. Our data suggest that neurons in the MS cortex are dying via TNF/TNFR1 stimulated necroptosis rather than apoptosis, possibly initiated in part by chronic meningeal inflammation. Neuronal necroptosis represents a pathogenetic mechanism that is amenable to therapeutic intervention at several points in the signaling pathway.

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Exploring the laminar connectome

10.1101/2021.03.17.21253439 ◽

2021 ◽

Author(s):

Ittai Shamir ◽

Omri Tomer ◽

Ronnie Krupnik ◽

Yaniv Assaf

Keyword(s):

White Matter ◽

Grey Matter ◽

Structural Description ◽

Mri Imaging ◽

Healthy Human ◽

Cortical Grey Matter ◽

Cortical Laminar ◽

White Matter Connectivity ◽

Human Brains

The human connectome is the complete structural description of the network of connections and elements that form the wiring diagram of the brain. Because of the current scarcity of information regarding laminar end points of white matter tracts inside cortical grey matter, tractography remains focused on cortical partitioning into regions, while ignoring radial partitioning into laminar components. To overcome this biased representation of the cortex as a single homogenous unit, we use a recent data-derived model of cortical laminar connectivity, which has been further explored and corroborated in the macaque brain by comparison to published studies. The model integrates multimodal MRI imaging datasets regarding both white matter connectivity and grey matter laminar composition into a laminar-level connectome. In this study we model the laminar connectome of healthy human brains (N=20) and explore them via a set of neurobiologically meaningful complex network measures. Our analysis demonstrates a subdivision of network hubs that appear in the standard connectome into each individual component of the laminar connectome, giving a fresh look into the role of laminar components in cortical connectivity and offering new prospects in the fields of both structural and functional connectivity.

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A higher proportion of ermin-immunopositive oligodendrocytes in areas of remyelination

PLoS ONE ◽

10.1371/journal.pone.0256155 ◽

2021 ◽

Vol 16 (8) ◽

pp. e0256155

Author(s):

Intakhar Ahmad ◽

Stig Wergeland ◽

Eystein Oveland ◽

Lars Bø

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Corpus Callosum ◽

Mouse Model ◽

Grey Matter ◽

Early Stage ◽

Relative Proportion ◽

Normal Appearing White Matter ◽

The Brain

Incomplete remyelination is frequent in multiple sclerosis (MS)-lesions, but there is no established marker for recent remyelination. We investigated the role of the oligodendrocyte/myelin protein ermin in de- and remyelination in the cuprizone (CPZ) mouse model, and in MS. The density of ermin+ oligodendrocytes in the brain was significantly decreased after one week of CPZ exposure (p < 0.02). The relative proportion of ermin+ cells compared to cells positive for the late-stage oligodendrocyte marker Nogo-A increased at the onset of remyelination in the corpus callosum (p < 0.02). The density of ermin-positive cells increased in the corpus callosum during the CPZ-phase of extensive remyelination (p < 0.0001). In MS, the density of ermin+ cells was higher in remyelinated lesion areas compared to non-remyelinated areas both in white- (p < 0.0001) and grey matter (p < 0.0001) and compared to normal-appearing white matter (p < 0.001). Ermin immunopositive cells in MS-lesions were not immunopositive for the early-stage oligodendrocyte markers O4 and O1, but a subpopulation was immunopositive for Nogo-A. The data suggest a relatively higher proportion of ermin immunopositivity in oligodendrocytes compared to Nogo-A indicates recent or ongoing remyelination.

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Regional brain volumes, microstructure and neurodevelopment in moderate–late preterm children

Archives of Disease in Childhood - Fetal and Neonatal Edition ◽

10.1136/archdischild-2019-317941 ◽

2020 ◽

Vol 105 (6) ◽

pp. 593-599 ◽

Cited By ~ 1

Author(s):

Claire E Kelly ◽

Deanne K Thompson ◽

Alicia J Spittle ◽

Jian Chen ◽

Marc L Seal ◽

...

Keyword(s):

White Matter ◽

Grey Matter ◽

Diffusion Tensor ◽

Brain Mri ◽

Developmental Outcomes ◽

Late Preterm ◽

Brain Volumes ◽

Regional Brain ◽

White Matter Microstructure ◽

Cortical Grey Matter

ObjectiveTo explore whether regional brain volume and white matter microstructure at term-equivalent age (TEA) are associated with development at 2 years of age in children born moderate–late preterm (MLPT).Study designA cohort of MLPT infants had brain MRI at approximately TEA (38–44 weeks’ postmenstrual age) and had a developmental assessment (Bayley Scales of Infant and Toddler Development and Infant Toddler Social Emotional Assessment) at 2 years’ corrected age. Relationships between cortical grey matter and white matter volumes and 2-year developmental outcomes were explored using voxel-based morphometry. Relationships between diffusion tensor measures of white matter microstructure (fractional anisotropy (FA) and axial (AD), radial (RD) and mean (MD) diffusivities) and 2-year developmental outcomes were explored using tract-based spatial statistics.Results189 MLPT children had data from at least one MRI modality (volumetric or diffusion) and data for at least one developmental domain. Larger cortical grey and white matter volumes in many brain regions, and higher FA and lower AD, RD and MD in several major white matter regions, were associated with better cognitive and language scores. There was little evidence that cortical grey matter and white matter volumes and white matter microstructure were associated with motor and behavioural outcomes.ConclusionsRegional cortical grey matter and white matter volumes and white matter microstructure are associated with cognitive and language development at 2 years of age in MLPT children. Thus, early alterations to brain volumes and microstructure may contribute to some of the developmental deficits described in MLPT children.

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Resolution of Left Hemisphere Cognitive Dysfunction in Multiple Sclerosis with Magnetic Resonance Correlates: A Case Report

Cognitive Neuropsychiatry ◽

10.1080/135468096396677 ◽

1996 ◽

Vol 1 (1) ◽

pp. 17-26 ◽

Cited By ~ 6

Author(s):

Leon Rozewicz

Keyword(s):

Multiple Sclerosis ◽

Case Report ◽

Magnetic Resonance ◽

Cognitive Dysfunction ◽

Left Hemisphere

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MULTI-MODAL MRI AT 7T TO DETECT AND QUANTIFY MULTIPLE SCLEROSIS CORTICAL GREY MATTER PATHOLOGY

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2012-304200a.137 ◽

2012 ◽

Vol 83 (Suppl 2) ◽

pp. A37.2-A37

Author(s):

OE Mougin ◽

N Mistry ◽

MM Papachatzaki ◽

P Gowland ◽

N Evangelou ◽

...

Keyword(s):

Multiple Sclerosis ◽

Grey Matter ◽

Cortical Grey Matter

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Psychiatric Symptoms Accompanying Multiple Sclerosis Onset: A Case Report

Journal of Neuropsychiatry ◽

10.1176/appi.neuropsych.13030055 ◽

2014 ◽

Vol 26 (2) ◽

pp. E06-E09

Author(s):

Elias Andreoulakis ◽

Ioannis Nimatoudis ◽

Ioanna Ierodiakonou-Benou ◽

Apostolos Iacovides

Keyword(s):

Multiple Sclerosis ◽

Case Report ◽

Psychiatric Symptoms ◽

Multiple Sclerosis Onset

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Different white matter lesion characteristics correlate with distinct grey matter abnormalities on magnetic resonance imaging in secondary progressive multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458509103176 ◽

2009 ◽

Vol 15 (6) ◽

pp. 687-694 ◽

Cited By ~ 8

Author(s):

J Furby ◽

T Hayton ◽

D Altmann ◽

R Brenner ◽

J Chataway ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Grey Matter ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive Multiple Sclerosis ◽

Lesion Volume ◽

Secondary Degeneration ◽

Secondary Progressive ◽

Demyelinating Lesions ◽

The Relationship

Background Although MRI measures of grey matter abnormality correlate with clinical disability in multiple sclerosis, it is uncertain whether grey matter abnormality measured on MRI is entirely due to a primary grey matter process or whether it is partly related to disease in the white matter. Methods To explore potential mechanisms of grey matter damage we assessed the relationship of white matter T2 lesion volume, T1 lesion volume, and mean lesion magnetisation transfer ratio (MTR), with MRI measures of tissue atrophy and MTR in the grey matter in 117 subjects with secondary progressive multiple sclerosis. Results Grey matter fraction and mean grey matter MTR were strongly associated with lesion volumes and lesion MTR mean ( r = ±0.63–0.72). In contrast, only weak to moderate correlations existed between white matter and lesion measures. In a stepwise regression model, T1 lesion volume was the only independent lesion correlate of grey matter fraction and accounted for 52% of the variance. Lesion MTR mean and T2 lesion volume were independent correlates of mean grey matter MTR, accounting for 57% of the variance. Conclusions Axonal transection within lesions with secondary degeneration into the grey matter may explain the relationship between T1 lesions and grey matter fraction. A parallel accumulation of demyelinating lesions in white and grey matter may contribute to the association of T2 lesion volume and lesion MTR with grey matter MTR.

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